Antiendotoxin activity of cationic peptide antimicrobial agents

Abstract

The endotoxin from gram-negative bacteria consists of a molecule lipopolysaccharide (LPS) which can be shed by bacteria during antimicrobial therapy. A resulting syndrome, endotoxic shock, is a leading cause of death in the developed world. Thus, there is great interest in the development of antimicrobial agents which can reverse rather than promote sepsis, especially given the recent disappointing clinical performance of antiendotoxin therapies. We describe here two small cationic peptides, MBI-27 and MBI-28, which have both antiendotoxic and antibacterial activities in vitro and in vivo in animal models. We had previously demonstrated that these peptides bind to LPS with an affinity equivalent to that of polymyxin B. Consistent with this, the peptides blocked the ability of LPS and intact cells to induce the endotoxic shock mediator, tumor necrosis factor (TNF), upon incubation with the RAW 264.7 murine macrophage cell line. MBI-28 was equivalent to polymyxin B in its ability to block LPS induction of TNF by this cell line, even when added 60 min after the TNF stimulus. Furthermore, MBI-28 offered significant protection in a galactosamine-sensitized mouse model of lethal endotoxic shock. This protection correlated with the ability of MBI-28 to reduce LPS-induced circulating TNF by nearly 90% in this mouse model. Both MBI-27 and MBI-28 demonstrated antibacterial activity against gram-negative bacteria in vitro and in vivo against Pseudomonas aeruginosa infections in neutropenic mice.

The novel β‐defensin DEFB123 prevents lipopolysaccharide‐mediated effectsin vitroandin vivo

“…In comparison, synthetic DEFB3 did not reduce LPSmediated activation of MAPK, albeit DEFB2 (i.e., hBD2) is known to have a similar effect as DEFB123 (42). The inhibition of LPS and the blocking of TNF-␣ was also reported for the ␣-helical peptide MBI-28 (43), which is in the same MW range. In addition, the structurally unrelated cathelicidin CAP18/LL-37 shows similar behavior (33).…”

The anti‐endotoxic effects of the KSL‐W decapeptide on Escherichia coli O55:B5 and various oral lipopolysaccharides

“…Cationic peptide binding to lipopolysaccharide has been well documented and has been related to a number of structural features contained within the peptide itself (16)(17)(18)36,(51)(52)(53)(54). Although specific charge groups and overall length of the peptide have been shown to be essential in the lipopolysaccharide-peptide binding interaction (11,12,15,55), increasing evidence is mounting which suggests that even small or shortened peptides (< 15 mers) retain significant lipopolysaccharide binding and immunomodulatory function (13,15,56).…”

“…Although multiple lipopolysaccharide effects have been reported to be obtunded by various types of anti-microbial peptides (16)(17)(18)36,(52)(53)(54)57), little is known about the effects on E-selectin expression or hemagglutination. The present study also showed that the decapeptide KSL-W, throughout a wide concentration range (25-200 lg/mL) was able to obtund the lipopolysaccharide-induced expression of E-selectin in human umbilical vein endothelial cells.…”

Anti-inflammatory activity of cationic peptides: application to the treatment of acne vulgaris

“…For example, several synthetic cationic antimicrobial peptides have been shown to block the LPS-and LTA-stimulated production of proinflammatory cytokines (e.g. TNF-a) by macrophages (Gough et al, 1996;Scott et al, 1999aScott et al, , 2000a. Dahlberg et al (1996) and Dankesreiter et al (2000) demonstrated that cationic antimicrobial peptides derived from various endotoxin-neutralizing proteins inhibited TNF-a release from LPS-stimulated macrophages.…”

“…Furthermore, Dahlberg et al (1996) and Dankesreiter et al (2000) showed that cationic peptides decreased plasma TNF-a levels in mice infected with Escherichia coli. Gough et al (1996) reported that the cationic peptide CEMA reduced the LPS-induced circulating TNF-a in a mouse model of lethal endotoxic shock. A similar effect was reported with the human antimicrobial peptide LL-37 (Scott et al, 2002).…”